tbuckley/cabot-search huggingface dataset:
CTNI-66. DECODING GLIOBLASTOMA SURVIVAL: UNRAVELING THE PROGNOSTIC POTENTIAL OF OLFACTORY FUNCTION IN A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Christoph Oster, Thomas Hummel, Elke Hattingen, Teresa Schmidt, Lazaros Lazaridis, Daniel Jokisch, Martha Jokisch, Sarina Agkatsev, Yahya Ahmadipour, Ulrich Sure, Martin Stuschke, Christoph Kleinschnitz, Björn Scheffler, Cornelius Deuschl, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Olfactory impairment is a common neurologic deficit among glioblastoma patients. We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function. A notable limitation in that study was the unequal distribution of prognostic factors between the two groups, and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity. Question: Can Olfactory Function Serve as an Independent Prognostic Indicator in Glioblastoma Patients? METHODS This prospective, multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls. Stratification of participants will be based on prognostically relevant variables such as resection status, MGMT promoter methylation status, radiographic involvement of olfactory brain areas, olfactory function, age, and Karnofsky performance status scale. We will utilize Sniffing Sticks to evaluate olfactory function through identification and threshold tests, and this assessment will be carried out longitudinally throughout the therapy starting from tumor diagnosis. Infiltration of the olfactory brain areas will be scrutinized using coronal T2 and T1 MRI sequences. MRI images will be independently reviewed by two board-certified radiologists from distinct institutions, who are blinded to the patients' olfactory function status. Furthermore, quality of life data, neuropsychological testing, and psychosomatic screening will be performed at specific intervals throughout the study. Also, we'll examine next-generation sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients. RESULTS The first participant was enrolled in May 2023. Plans are underway to open a second study site in 2024, with the aim to complete recruitment by December 2025. Follow-up assessments will continue until December 2027. We anticipate that the final results of the study will be available in 2028.
SURG-18. ONCO-FUNCTIONAL OUTCOME AFTER RESECTION FOR ELOQUENT GLIOBLASTOMA (GLIOFO STUDY): A PROPENSITY-SCORED ANALYSIS OF AN INTERNATIONAL, MULTICENTER COHORT STUDY
Authors: Jasper Gerritsen, Rania Mekary, Dana Pisica, Rosa Zwarthoed, John Kilgallon, Noah Nawabi, Charissa Jessurun, Georges Versyck, Koen Pruijn, Fleur Fisher, Emma Larivière, Lien Solie, Alfred Kloet, Rishi Nandoe Tewarie, Joost Schouten, Eelke Bos, Timothy Smith, Clemens Dirven, Marike Broekman, Arnaud Vincent, Steven De Vleeschouwer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Minimizing residual tumor volume and preventing functional loss are the primary goal in glioblastoma resections in eloquent areas. However, their combined impact on patient outcomes remains poorly understood. We therefore developed a novel onco-functional outcome (OFO) classification and evaluated its benefit in subgroups based on age, preoperative neurological morbidity (NIHSS), and preoperative Karnofsky Performance Score (KPS). METHODS Propensity-score matching was used to match OFO 1 (no residual volume, no postoperative functional loss) vs. non-OFO 1 patients for the overall cohort and subgroups based on age, NIHSS, and KPS. Cox proportional-hazard regressions were performed to analyze the association between OFO class and postoperative neurological deficits, KPS deterioration, receipt of adjuvant therapy, overall survival, and progression-free survival. Logistic regressions were performed to analyze the predictive value of perioperative factors on OFO class. Findings Between 2010 and 2020, 858 patients with tumor resection for primary eloquent glioblastoma were included as the overall unmatched cohort. After matching, the overall matched cohort comprised of 512 patients: 256 received OFO 1 and 256 received non-OFO 1. In the overall matched cohort and matched subgroups, OFO 1 resulted in fewer postoperative neurological deficits, lower rates of postoperative KPS deterioration, higher rates of receipt of adjuvant therapy, longer overall survival (median 21.0 months vs. 13.0 months, p &amp;lt; 0.001), and longer progression-free survival (median 10.0 months vs. 7.5 months, p &amp;lt; 0.001). Patients who underwent awake craniotomy more often received OFO 1 (43.0% vs. 26.9%, p &amp;lt; 0.001), and awake craniotomy was an independent predictor for OFO 1 (OR 1.93, p = 0.0070). Interpretation OFO 1 is beneficial in patients with glioblastoma in eloquent areas to improve surgical outcomes, irrespective of age, preoperative NIHSS, or KPS. Furthermore, awake craniotomy was significantly associated with achieving this status. These results might aid neurosurgeons with their surgical decision making in individual patients.
RADT-34. CLINICAL OUTCOMES OF LOCALISED AND METASTATIC CENTRAL NERVOUS SYSTEM HAEMANGIOPERICYTOMAS/SOLITARY FIBROUS TUMOURS – A SINGLE INSTITUTION EXPERIENCE
Authors: Jeyaanth Venkatasai, Vishal Manik, Kazumi Chia, Angela Swampillai, Omar Al-Salihi, Lucy Brazil
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND/OBJECTIVE Central nervous system (CNS) haemangiopericytomas (HPC) or solitary fibrous tumours (SFT) are rare aggressive tumours. Surgery is the primary modality of treatment, however, often followed by postoperative radiotherapy due to high tendency for local recurrence. Although rare, extracranial metastases to several sites have been described. We aim to report our institutional experience in managing these rare tumours. METHODS Patients with central nervous system HPC/SFT who underwent surgical resection from 2012 to 2022 were included in the study. Data collected included patient demographics, tumour characteristics, treatment details (including primary surgery, radiotherapy and treatment for relapse) and clinical outcomes. RESULTS Five patients were included in this study. All were women and their mean age at diagnosis was 43 years. Four patients presented with intracranial disease and one with cervico-thoracic spine disease. All patients had undergone primary surgery and gross total resection was achieved in two patients. Two patients had grade 1, one with grade 2 and two with grade 3 HPC. Four patients received radiotherapy (median dose 60Gy) and one was on imaging surveillance after surgery. Three patients had relapsed – one with locoregional relapse only, one with distant (liver and bone) relapse and other with locoregional and distant (lung and bone). Time to relapse were 192, 39 and 120 months respectively. Stereotactic radiotherapy was used to treat local relapse in posterior fossa and dura of cervical spine, and metastatic relapse in lung with a stable radiological response. One patient with a painful destructive bone metastases was treated with palliative radiotherapy with good pain control. Four patients were alive at the time of the study, and one was lost to follow up. CONCLUSION We present our institutional experience in management of localised and metastatic HPC/SFT. Stereotactic radiotherapy could be considered an effective treatment modality for small volume relapse of HPC.
TMIC-78. ENDOTHELIAL REGULATION OF THE IMMUNOSUPPRESSIVE PHENOTYPE OF TUMOR-ASSOCIATED MICROGLIA IN GLIOBLASTOMA
Authors: Sree Deepthi Muthukrishnan, Haocheng Qi, Alvaro Alvarado, Riki Kawaguchi, Harley Kornblum
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is considered a non-immunogenic “cold tumor” with an immunosuppressive microenvironment that blocks T-cell infiltration and function, limiting the efficacy of targeted immunotherapy. Tumor-associated microglia and macrophages (TAM) constitute approximately 30-50% of the non-neoplastic immune cells, and they are closely associated with blood vessels in GBM. However, the precise mechanism by which TAM acquire the immunosuppressive phenotype remains poorly understood. In this study, we show that tumor endothelial cells (TEC) from primary and recurrent GBM express inflammatory cytokines and chemokines that influence the function and polarization of microglia. We demonstrate that conditioned media (CM) of TEC promotes the immunosuppressive phenotype of normal microglia and patient-derived TAM. RNA-sequencing of TAM treated with TEC-CM shows upregulation of immunosuppressive cytokines, as well as T-cell co-inhibitory molecules such as PD-L1. Culturing CD8 T-cells in CM of TAM-polarized by TEC inhibits their cytotoxic function and cytokine production, and induces expression of PD-1 and CTLA-4. Furthermore, gene set enrichment analysis uncovers alterations in calcium signaling-related pathways in TAM polarized by TEC-CM. Blocking calcium signaling with small molecule inhibitors in microglia reverses the immunosuppressive phenotype induced by TEC. To determine whether the interactions between GBM, endothelial cells and TAM promotes immunosuppression in vivo, we utilize the humanized immune system mouse model (huNOG-EXL) that harbor human lymphocytes and monocyte populations. In preliminary studies, we found that co-transplantation of GBM tumor cells with TAM and TEC significantly promotes tumor growth compared with GBM cells alone. Single-cell mass cytometry analysis of peripheral blood mononuclear cells (PBMC) pre- and post-transplant, and scRNA-sequencing and spatial-transcriptomic studies of these co-transplanted mice will potentially reveal key insights into local- and peripheral immune responses regulated by tumor endothelial-microglia interactions. Together, our findings highlight a key role for endothelial-mediated calcium signaling in regulation of the immunosuppressive phenotype of microglia in GBM.
NIMG-67. REVISITING GLIOMATOSIS CEREBRI IN ADULT-TYPE DIFFUSE GLIOMAS: A COMPREHENSIVE ANALYSIS OF MANIFESTATION AND RISK FACTORS IN THE 2021 WHO CLASSIFICATION
Authors: Ilah Shin, Yae Won Park, Sung Soo Ahn, Jong Hee Chang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND To investigate the incidence, clinicopathologic and imaging correlations and prognostic implications of gliomatosis cerebri (GC) pattern in adult-type diffuse glioma patients reflecting the 2021 WHO classification. METHODS Retrospective chart and imaging review was performed in 1,211 adult-type diffuse glioma patients at a single institution between 2005 and 2021. Clinicopathologic and imaging features were compared amongst adult-type diffuse glioma patients with and without GC based on the 2021 WHO classification. Clinical and imaging risk factors for predicting IDH mutation status within GC patients were investigated. Survival analysis was performed in entire patients and in subgroup of IDH-wildtype glioblastoma patients to evaluate whether GC is an independent prognostic factor. RESULTS Total 99 patients (8.9% of entire patients) showed GC. The distribution of tumor type was significantly different in patients with GC compared with those without GC (P = 0.017); IDH-wildtype glioblastoma being most common (77.8% vs. 68.9%), followed by IDH-mutant astrocytoma (16.2% vs 16.9%), and being less common in oligodendroglioma (6.1% vs 16.5%). Contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR=1.55, P=0.031) in IDH-wildtype glioblastoma patients on multivariable analyses. CONCLUSIONS The incidence of GC is 8.9% in adult-type diffuse gliomas, with IDH-wildtype glioblastoma showing significantly higher risk of GC. Preoperative imaging features may predict IDH mutation status in GC patients. GC is an independent prognostic factor in IDH-wildtype glioblastoma, and promote recognition of this pattern in clinical settings.
INNV-39. INVESTIGATING MULTI-AGENT INTRATHECAL CHEMOTHERAPY AS A TREATMENT FOR PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA: SAFETY AND EFFICACY RESULTS FROM AN INSTITUTIONAL COHORT STUDY
Authors: Hannah Wilding, Aastha Aastha, Leonardo Jose Monteiro De Macedo Filho, Debarati Bhanja, Madison Heebner, Shahbaz Khan, Nicholas Mikolajewicz, Vladimir Ignatchenko, Thomas Kislinger, Michael Glantz, Alireza Mansouri
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Despite exquisite responses to initial therapy for CNS lymphoma, relapse is common and overall responses are disappointing compared to non-CNS diffuse large B-cell lymphomas. Literature reports 1 and 3 year survival rates of 50% and 30-40% respectively, with standard treatment. Intravenous, high-dose-methotrexate-based therapies have become the standard of care, with many variations but no consensus. Incorporation of multi-agent intrathecal chemotherapy (MAITC) alongside systemic therapy is novel but not widely adopted. We report our institutional data on safety and efficacy of MAITC in CNS lymphoma. METHODS A retrospective review of patients with primary or secondary CNS lymphoma, treated with MAITC between August 2015 and December 2021, was conducted. Each cycle includes alternating combinations of 2-3 of the following drugs: methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, and thiotepa, via ommaya reservoir. Log-rank tests and Cox regression were used to evaluate survival differences. RESULTS 59 patients were reviewed (21 primary; 38 secondary CNS lymphoma). Median age at start of MAITC was 66 years (range 25-90). Only six patients received external beam radiation (EBRT). Median MAITC cycles was 8 (range 2-23). 76% of patients with primary and 66% with secondary CNS lymphoma were alive 1 year after starting MAITC. Of 37 eligible patients, 17 (46%) were alive 3 years after starting MAITC. After a median 19.2 months follow-up, median OS was not reached. No significant difference was noted in OS between primary and secondary CNS lymphoma. KPS &amp;gt; 80 was positively while leptomeningeal disease, secondary CNS lymphoma, and EBRT were negatively associated with OS. Ommaya-related infections occurred in 8 patients (13.5%); only 1 required removal. CONCLUSION Based on our institutional data, MAITC can potentially offer a significant OS advantage with minimal safety concerns. Factors associated with poor survival were identified, which are being addressed in a larger dataset along with baseline CSF biomarkers.
SURG-27. 17-YEAR EXPERIENCE OF SURGICAL MANAGEMENT OF INTRADURAL EXTRAMEDULLARY (IDEM) TUMORS: CLINICAL OUTCOMES FROM A LOW- AND MIDDLE-INCOME COUNTRY
Authors: Ahmad Ozair, Vinay Suresh, H S Suresh, Bharath Raju, Manmeet Ahluwalia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Surgical outcomes of intradural extramedullary (IDEM) tumors have been well-reported in the literature from high-income countries. However, limited contemporaneous data from low- and middle-income countries (LMICs) exists. This study sought to analyze the clinical outcomes of all IDEM tumor cases operated during a 17-year period at a resource-limited setting in an LMIC. METHODS The present work was conducted and reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. A retrospective cohort study was carried out to analyze all IDEM tumor cases, operated upon by a consultant neurosurgeon, during 2004-2021, at a resource-limited setting in Southern India. All patients underwent routine biochemical and radiological investigations, including contrast-enhanced MRI. Laminectomy and tumor resection under the microscope were done without using intraoperative neuro-monitoring. Nerve fibers running through the tumor were sacrificed. Bilateral facet joints were preserved to ensure integrity without spinal fusion. All cases received a dural closure with 5-0 Prolene, with postoperative MRI confirming complete resection. Patients received telephonic and/or in-person follow-up visits. RESULTS 50 patients with a mean age of 46.3 years (range 13-80) were included, with 31 males and 19 females. Their clinical presentation included radiculopathy (78%), radiculomyelopathy (12%), and radiculomyelopathy with bowel and bladder symptoms (10%). Histologically, schwannomas were the most common (52%), followed by neurofibromas (34%), meningiomas (12%), and ependymomas (2%). Two individuals were diagnosed with Neurofibromatosis Type 1. All meningiomas occurred in the thoracic region, with 83.3% of cases being in females. All patients had symptomatic relief postoperatively. No major adverse events occurred, including CSF leaks, permanent neurological deficits, or spinal instability. Recurrence occurred in two 'dumbbell' tumors (4%) at 5 and 7 years after primary excision during follow-up, managed with successful re-resection. CONCLUSION Microsurgical excision of IDEM tumors carries high safety and efficacy, including in resource-limited settings like LMICs.
MODL-26. A PROTOCOL TO ADAPT GLIOBLASTOMA IN VITRO CULTURE SYSTEMS INTO ORGANOID MODELS USING NEUROCULT™ NS-A PROLIFERATION MEDIUM
Authors: Kasandra McCormack, Carmen Mak, Allen Eaves, Sharon Louis, Erin Knock
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a malignant and aggressive brain tumor that is difficult to treat due to its heterogeneity. Traditional in vitro models (i.e. monolayers and tumorspheres) do not recapitulate this heterogeneity, leading to difficulty assessing new therapeutic strategies. Culturing GBM cells as organoids may provide a better method to retain the phenotype of the parent tumor. Here, we present a protocol for generating GBM organoids using NeuroCult™ NS-A Proliferation Medium, a medium commonly used for tumorsphere cultures. Two methods were assessed for the initial stage of formation, each suitable depending on throughput and cell source. In the first method, tumorspheres were dissociated and single cells were mixed with Growth Factor Reduced Matrigel® at a 1:4 ratio to form 15 μL droplets with 1000 cells per droplet. In the second method, 9000 cells from dissociated tumorspheres were seeded per well in a 96-well U-bottom plate and cultured for 5 days to form aggregates. On day 6, the aggregates were embedded in 15 μL Matrigel® droplets. In both methods, polymerized droplets were then cultured in suspension in stationary 6-well plates for 3 days, then maintained on an orbital shaker with full-medium changes every 2 - 3 days. Organoids were cryosectioned and processed for immunofluorescence at 5 - 6 weeks. In vivo, GBM tumors display an architecture containing regions of high and low nutrient and oxygen availability around a necrotic core. GBM organoids generated using this protocol exhibited distinct areas of proliferation near the organoid rim (Ki67+) and hypoxia (CA9+) near the core, mimicking this in vivo architecture (n = 3 GBM cell lines). Organoids grew to 2 - 4 mm in diameter and expressed glioma markers including TUJ1, Nestin, SOX2, OLIG2, and GFAP. These data show that NeuroCult™ NS-A Proliferation Medium can be used to adapt traditional GBM culture systems into organoids.
CTNI-77. POST-PROGRESSION TREATMENT AFTER VAL-083 WITH RADIATION IN NEWLY DIAGNOSED GBM MGMT UNMETHYLATED PATIENTS
Authors: Cheng-chen Guo, Qun-ying Yang, Shao-yan Xi, Yi-Xiang Liao, De-pei Li, Xiao-bing Jiang, Yin-sheng Chen, Chao Ke, Ke Sai, Richard Schwartz, John Langlands, Dennis Brown, Zhongping Chen
Journal: Neuro-Oncology (2023)

Abstract VAL-083 is a novel DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and thus differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM. Stage 1 was a dose-escalation to confirm the dose of VAL-083 in this setting; VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083.
IMMU-33. PRECISION ANTIGEN-DIRECTED IMMUNOTHERAPY TREATMENT OF BRAIN TUMORS INCREASES TUMOR-INFILTRATING EFFECTOR LYMPHOCYTE RESPONSES
Authors: Vrunda Trivedi, Changlin Yang, Oleg Yegorov, Kelena Klippel, Christina Von Roemeling, Lan Hoang-Minh, Graeme Fenton, Elizabeth Ogando-Rivas, Paul Castillo, Ginger Moore, Kyle Dyson, Duane Mitchell
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Despite considerable advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized tumor antigens expressed within brain tumors that can mediate tumor rejection; the limited mutational burden within these cancers that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. Our OBJECTIVE is to develop a precision immunotherapy approach for brain tumor patients utilizing prospectively identified tumor-specific antigens using cancer immunogenomics and selective amplification of patients’ tumor-specific antigens for generating tumor antigen-specific lymphocyte therapy. METHODS We identified neoantigens and tumor-associated antigens that were uniquely expressed in preclinical glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (ORAN). A tumor antigen-specific RNA library was created for each tumor model and tumor-bearing animals were treated with ex vivo expanded tumor-specific lymphocytes and tumor antigen-specific RNA-loaded dendritic cell (tsRNA-DC) vaccines. In a different approach, animals were treated with a combination of tsRNA-DC vaccines and anti-PD-1 checkpoint-blockade therapy. Tumor progression and survival outcomes were determined. The immune cell response was evaluated using flow cytometry, TCR sequencing, and single-cell RNAseq. RESULTS Our results demonstrate the effectiveness of tsRNA-DC vaccines in eliciting robust anti-tumor immune responses in combination with adoptive cellular therapy and checkpoint blockade therapy. Additionally, our findings substantiate a robust increase in tumor-infiltrating lymphocytes characterized by enhanced effector function both intratumorally and systemically after tumor antigen-specific RNA-directed immunotherapies. CONCLUSION This powerful approach to generating immunotherapy recognizing a plurality of tumor antigens uniquely addresses the challenge of dealing with tumor antigenic heterogeneity and confronting the reality of patient-to-patient variation in antigen expression in the development of antigen targeting strategies.